DNA-Methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Krüppel-Like Factor 4 Expression.
DNA-Methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Krüppel-Like Factor 4 Expression.
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DOI：
10.1158/1078-0432.ccr-17-0387
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发表时间：
2017-09-15
期刊：
影响因子：
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通讯作者：
Wei D
中科院分区：
文献类型：
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作者：
Xie VK;Li Z;Yan Y;Jia Z;Zuo X;Ju Z;Wang J;Du J;Xie D;Xie K;Wei D
胰腺癌预后差与肿瘤分化差有关。然而，胰腺癌分化的分子基础和潜在的治疗价值的基础分子仍然未知。我们研究了Krüppel样因子4（KLF 4）在胰腺癌中的低表达机制，并确定了一种新的胰腺癌分化和治疗的表观遗传激活途径。采用免疫组织化学方法检测胰腺癌组织中KLF 4和DNMT 1的表达，并应用分子生物学技术研究KLF 4在胰腺癌中的遗传学和表观遗传学改变以及KLF 4对胰腺癌分化的影响。使用细胞培养和动物模型评估膳食3，3 '-二吲哚基甲烷（DIM）对胰腺癌中miR-152/DNMT 1/KLF 4信号传导的功能。DNMT 1过表达和启动子甲基化导致KLF 4表达降低，并与胰腺癌的低分化相关。KLF 4表达的操纵显著影响胰腺癌细胞中分化标志物的表达。DIM处理显著诱导miR-152表达，从而阻断DNMT 1蛋白表达及其与KLF 4启动子区域的结合，从而降低启动子DNA甲基化并激活胰腺癌细胞中KLF 4的表达。此外，DIM处理引起体外细胞生长和胰腺癌动物模型中肿瘤发生的显著抑制。这是首次证明KLF 4表达失调与胰腺癌的低分化有关。饮食DIM对miR-152/DNMT 1/KLF 4信号通路的表观遗传激活导致胰腺癌细胞分化和显著生长抑制，突出了其对胰腺癌和其他癌症的翻译意义。
The dismal prognosis of pancreatic cancer has been linked to poor tumor differentiation. However, molecular basis of pancreatic cancer differentiation and potential therapeutic value of the underlying molecules remain unknown. We investigated the mechanistic underexpression of Krüppel-like factor 4 (KLF4) in pancreatic cancer and defined a novel epigenetic pathway of its activation for pancreatic cancer differentiation and treatment. Expressions of KLF4 and DNMT1 in pancreatic cancer tissues were determined by immunohistochemistry and the genetic and epigenetic alterations of KLF4 in and KLF4’s impact on differentiation of pancreatic cancer were examined using molecular biology techniques. The function of dietary 3,3’-diindolylmethane (DIM) on miR-152/DNMT1/KLF4 signaling in pancreatic cancer was evaluated using both cell culture and animal model. Overexpression of DNMT1 and promoter hypermethylation contributed to decreased KLF4 expression in and associated with poor differentiation of pancreatic cancer. Manipulation of KLF4 expression significantly affected differentiation marker expressions in pancreatic cancer cells. DIM treatment significantly induced miR-152 expression, which blocked DNMT1 protein expression and its binding to KLF4 promoter region, and consequently, reduced promoter DNA methylation and activated KLF4 expression in pancreatic cancer cells. Additionally, DIM treatment caused significant inhibition of cell growth in vitro and tumorigenesis in animal model of pancreatic cancer. This is the first demonstration that dysregulated KLF4 expression associates with poor differentiation of pancreatic cancer. Epigenetic activation of miR-152/DNMT1/KLF4 signaling pathway by dietary DIM causes differentiation and significant growth inhibition of pancreatic cancer cells, highlighting its translational implications for pancreatic and other cancers.